Molecular Mechanism of Resolving Trinucleotide Repeat Hairpin by Helicases

Yupeng Qiu; Hengyao Niu; Lela Vukovic; Patrick Sung; Sua Myong

doi:10.1016/j.str.2015.04.006

Molecular Mechanism of Resolving Trinucleotide Repeat Hairpin by Helicases

Yupeng Qiu, Hengyao Niu, Lela Vukovic, Patrick Sung, Sua Myong

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Summary Trinucleotide repeat (TNR) expansion is the root cause for many known congenital neurological and muscular disorders in human including Huntington's disease, fragile X syndrome, and Friedreich's ataxia. The stable secondary hairpin structures formed by TNR may trigger fork stalling during replication, causing DNA polymerase slippage and TNR expansion. Srs2 and Sgs1 are two helicases in yeast that resolve TNR hairpins during DNA replication and prevent genome expansion. Using single-molecule fluorescence, we investigated the unwinding mechanism by which Srs2 and Sgs1 resolves TNR hairpin and compared it with unwinding of duplex DNA. While Sgs1 unwinds both structures indiscriminately, Srs2 displays repetitive unfolding of TNR hairpin without fully unwinding it. Such activity of Srs2 shows dependence on the folding strength and the total length of TNR hairpin. Our results reveal a disparate molecular mechanism of Srs2 and Sgs1 that may contribute differently to efficient resolving of the TNR hairpin.

Original language	English (US)
Article number	3163
Pages (from-to)	1018-1027
Number of pages	10
Journal	Structure
Volume	23
Issue number	6
DOIs	https://doi.org/10.1016/j.str.2015.04.006
State	Published - Jun 3 2015
Externally published	Yes

ASJC Scopus subject areas

Molecular Biology
Structural Biology

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title = "Molecular Mechanism of Resolving Trinucleotide Repeat Hairpin by Helicases",

abstract = "Summary Trinucleotide repeat (TNR) expansion is the root cause for many known congenital neurological and muscular disorders in human including Huntington's disease, fragile X syndrome, and Friedreich's ataxia. The stable secondary hairpin structures formed by TNR may trigger fork stalling during replication, causing DNA polymerase slippage and TNR expansion. Srs2 and Sgs1 are two helicases in yeast that resolve TNR hairpins during DNA replication and prevent genome expansion. Using single-molecule fluorescence, we investigated the unwinding mechanism by which Srs2 and Sgs1 resolves TNR hairpin and compared it with unwinding of duplex DNA. While Sgs1 unwinds both structures indiscriminately, Srs2 displays repetitive unfolding of TNR hairpin without fully unwinding it. Such activity of Srs2 shows dependence on the folding strength and the total length of TNR hairpin. Our results reveal a disparate molecular mechanism of Srs2 and Sgs1 that may contribute differently to efficient resolving of the TNR hairpin.",

author = "Yupeng Qiu and Hengyao Niu and Lela Vukovic and Patrick Sung and Sua Myong",

note = "Funding Information: We thank the Myong Laboratory members for helpful discussions and Jordan Billingsley for editing the manuscript. Support for this work was provided by NIH Director{\textquoteright}s New Innovator Award (343 NIH 1 DP2 GM105453 A) and American Cancer Society (Research Scholar Grant; RSG-12-066-01-DMC) for S. M. and Y. Q. Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd.",

year = "2015",

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doi = "10.1016/j.str.2015.04.006",

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AU - Qiu, Yupeng

AU - Niu, Hengyao

AU - Vukovic, Lela

AU - Sung, Patrick

AU - Myong, Sua

N1 - Funding Information: We thank the Myong Laboratory members for helpful discussions and Jordan Billingsley for editing the manuscript. Support for this work was provided by NIH Director’s New Innovator Award (343 NIH 1 DP2 GM105453 A) and American Cancer Society (Research Scholar Grant; RSG-12-066-01-DMC) for S. M. and Y. Q. Publisher Copyright: © 2015 Elsevier Ltd.

PY - 2015/6/3

Y1 - 2015/6/3

N2 - Summary Trinucleotide repeat (TNR) expansion is the root cause for many known congenital neurological and muscular disorders in human including Huntington's disease, fragile X syndrome, and Friedreich's ataxia. The stable secondary hairpin structures formed by TNR may trigger fork stalling during replication, causing DNA polymerase slippage and TNR expansion. Srs2 and Sgs1 are two helicases in yeast that resolve TNR hairpins during DNA replication and prevent genome expansion. Using single-molecule fluorescence, we investigated the unwinding mechanism by which Srs2 and Sgs1 resolves TNR hairpin and compared it with unwinding of duplex DNA. While Sgs1 unwinds both structures indiscriminately, Srs2 displays repetitive unfolding of TNR hairpin without fully unwinding it. Such activity of Srs2 shows dependence on the folding strength and the total length of TNR hairpin. Our results reveal a disparate molecular mechanism of Srs2 and Sgs1 that may contribute differently to efficient resolving of the TNR hairpin.

AB - Summary Trinucleotide repeat (TNR) expansion is the root cause for many known congenital neurological and muscular disorders in human including Huntington's disease, fragile X syndrome, and Friedreich's ataxia. The stable secondary hairpin structures formed by TNR may trigger fork stalling during replication, causing DNA polymerase slippage and TNR expansion. Srs2 and Sgs1 are two helicases in yeast that resolve TNR hairpins during DNA replication and prevent genome expansion. Using single-molecule fluorescence, we investigated the unwinding mechanism by which Srs2 and Sgs1 resolves TNR hairpin and compared it with unwinding of duplex DNA. While Sgs1 unwinds both structures indiscriminately, Srs2 displays repetitive unfolding of TNR hairpin without fully unwinding it. Such activity of Srs2 shows dependence on the folding strength and the total length of TNR hairpin. Our results reveal a disparate molecular mechanism of Srs2 and Sgs1 that may contribute differently to efficient resolving of the TNR hairpin.

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Molecular Mechanism of Resolving Trinucleotide Repeat Hairpin by Helicases

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